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Introduction: The neutrophil-to-lymphocyte ratio (NLR) has previously been reported to be associated with survival in ALS. To provide further information about the role of NLR as a biomarker in ALS, we performed a systematic review, analyzed data from our local cohort of ALS subjects and performed a meta-analysis. Methods: (Citation1) The systematic review used established methods. (Citation2) Using data from our cohort of subjects, we analyzed the association of NLR with survival. (Citation3) Meta-analysis was performed using previous studies and our local data. Results: (Citation1) In the systematic review, higher NLR was associated with shorter survival in all studies. (Citation2) In our subjects, survival was significantly shorter in patients in the highest NLR groups. (Citation3) Meta-analysis showed subjects with highest NLR tertile or with NLR >3 had significantly shorter survival than other subjects. Discussion: This study supports NLR as a biomarker in ALS; high NLR is associated with poor survival.
1. Introduction
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive upper and lower motor neurone weakness, leading to death by respiratory failure (Citation1, Citation2). The duration of survival of patients is variable (Citation3). Survival is shorter in bulbar disease, in older patients and in females (Citation4–7). Long survival (greater than five years) is more common in males, in those with spinal onset, and in non-classical ALS (Citation6, Citation8–11). There are models, such as the SEALS (Citation12) and ENCALS (Citation13) models, that predict survival. Prognostic biomarkers include spirometry (Citation5), decline in function (Citation14), and King’s stage criteria (Citation15).
There is a need for biomarkers that are easily obtainable. Blood is easily accessible, and many blood biomarkers are reported (Citation16–18). Blood level of neurofilament light is a promising biomarker (Citation19, Citation20), and low numbers of circulating regulatory T cells (Citation21, Citation22) are associated with poor survival; however, these measurements are not available in routine practice.
The neutrophil-to-lymphocyte ratio (NLR), readily available from routine tests, is an established clinical biomarker for “stress-responses” (Citation23–25). NLR has been associated with survival in ALS (Citation26–29). The present study aims to provide further information about NLR as a biomarker in ALS. We performed a systematic review, investigated the association between survival and NLR in our local cohort, and performed a meta-analysis of studies from the systematic review together with the results from our cohort.
2. Methodology
2.1. Systematic review
The aim was to find papers that studied NLR as a biomarker in ALS. The PRISMA guidelines were used (Citation30). The QUADAS-2 qualitative assessment was applied (Citation31). The inclusion criteria were: study is original, study subjects are humans aged 18 years or older; the diagnosis is made using established criteria (Citation32–34); study analyses NLR with outcomes including survival; study is a full text journal article published in English; study provides sufficient description of methods. The exclusion criteria were: studies without NLR association with ALS or MND; studies without disease duration; studies without clear methods, animal studies; studies not in English.
The database search was performed on 15th January 2024. We searched for the terms neutrophil-to-lymphocyte ratio, and amyotrophic lateral sclerosis (ALS) or motor neurone disease (MND).
2.2. Queensland ALS cohort
Data was collected from subjects attending the Motor Neurone Disease Clinic, Royal Brisbane & Women’s Hospital. All subjects had ALS based on established criteria (Citation32–34). We selected subjects with information about the earliest NLR after diagnosis, age of onset, date of death or censoring, region of onset, disease type, sex and family history of ALS. For some of these subjects we also had information about results of spirometry, body mass index and ALSFRS-R score soon after diagnosis.
Survival was calculated from date of symptom onset to date of death or censoring. Since the date of onset of ALS is not always precise, and NLR data is collected at varying times after the onset of disease, we also performed analysis using survival calculated from the date of the NLR to the date of death or censoring. Since sex affects survival (Citation6, Citation35), we also analyzed NLR and survival in males and females.
Categorical variables were analyzed with Pearson’s chi square test, continuous variables with the Mann-Whitney test and Mantel-Cox analysis. A significant p-value was <0.05. Survival was displayed with Kaplan-Meier curves and scatter plot. The Cox regression model was used to analyze survival with continuous and categorical variables.
To investigate the sensitivity and specificity of the NLR we plotted survival curves for each tertile. We also performed a ROC analysis to investigate the association of NLR with survival for two and for five years from the date of the test. We have previously considered survival of < 2 years to be short survival and survival of >5 years to be long survival (Citation6).
2.3. Meta-analysis
We performed two meta-analyses. One meta-analysis is for studies with NLR shown as tertiles, and the other meta-analysis is for studies with NLR grouped according to cutoff values.
The Comprehensive Meta-Analysis software version 3.3.1 (Biostat, USA) was used for the meta-analysis, comparing mean (± standard deviation) survival values from study survival analysis. If the studies reported median survival values (with interquartile range), these values were converted to estimated mean values using established methods (Citation36–39). For each study, the mean survival of each group was compared with mean survival of the full cohort. The random effect model was applied with heterogeneity expressed as I2.
3. Results
3.1. Systematic review
The process of the systematic review is shown in and Supplementary Data Citation1. Eleven studies were assessed for eligibility (Citation24, Citation26–29, Citation40–45). Two studies were excluded as they reported levels of leukocytes or neutrophils as absolute measurements rather than NLR (Citation43,Citation45)
Figure 1. Flow chart showing search strategy and the number of papers in the systematic review.
summarizes the studies that showed NLR in ALS, and the analyses that were performed. One study showed that NLR was associated with ALS progression shown as functional biomarkers (Citation24), and another showed NLR was associated with ALS progression as clinical assessment (Citation44). Six studies reported regression analysis of the assocation of NLR with survival, as shown in , and in . All studies showed that higher NLR increases risk of death.
Figure 2. This figure shows the hazard ratios reported in the studies identified in the systematic review together with the hazard ratio calculated from our local cohort. The hazard ratios were calculated using Cox-Proportional-Hazard-Ratios.
Table 1. Summary of studies of NLR and ALS survival identified by systematic review.
Table 2. Cox-proportional-hazards regression analysis results in studies identified by systematic review.
Four studies reported survival analysis as Kaplan-Meier curves and Cox regression survival analyses. Two studies categorized subjects into as NLR tertiles (Citation26, Citation28), and two studies grouped subjects based on NLR of < 2, 2 − 3, and > 3 (Citation27, Citation29), as has been used other in studies (Citation46). These results are summarized in and Supplementary Data Citation2. In all studies, the subjects in the group with the greatest NLR showed shorter survival.
Table 3. NLR at diagnosis and survival in the four studies included for meta-analysis: Kaplan-Meier and Cox-proportional-hazards regression analysis results.
3.2. NLR and survival in Queensland ALS cohort
3.2.1. Full cohort comparison
Our database contained 822 ALS patients (701 deceased) who had complete information about date of symptom onset, date of diagnosis and date of death or censoring, and NLR at diagnosis. We decided analyzed our data according to tertiles and in groups according to cutoff values. We first present the analysis of our cohort according to tertiles ().
Table 4. Characteristics of Queensland ALS cohort shown in NLR tertiles.
The overall median age of disease onset (62 years) was different across NLR tertiles (p < 0.0001). Comparison of NLR and early and late onset was significant in NLR T1 vs T3 (p < 0.05). The NLR did not show significant association with region of onset, disease type, family history of ALS, FVC, body mass index or ALSFRS-R score.
The overall median survival from date of symptom onset was significanly greater in T1 (39 months) vs T3 (30 months) (p = 0.0006), and T2 (37 months) vs T3 (p = 0.0065). This is shown as Kaplan-Meier curves in . The coefficient variation (R2) of survival and NLR was low, as shown as a scatter plot in .
Figure 3. Kaplan-Meier Curves and Scatter Plots comparing NLR tertiles and survival of the Queensland ALS Cohort from date of symptom onset, and date of first NLR. TOP: Kaplan-Meier curves comparing the NLR tertiles with log survival - T3 showing significantly poorer survival in both. BOTTOM Scatter plots showing survival and NLR for the cohort– R2 = 0.016 for date of symptom onset, and R2 = 0.023 for date of NLR. These both indicate low overall association between survival and NLR.
We also analyzed survival of NLR tertiles from date of first NLR. Survival was significantly longer in T1 (26 months) vs T3 (12 months), and T2 (20 months) vs T3 (Mann-Whitney (p < 0.0001—0.0013) and Mantel-Cox (p < 0.001)) ( – upper panel). Coefficient variation (R2) of survival and NLR was low (-lower panel).
The univariable Cox regression, from date of symptom onset, is summarized in . For NLR T3/T1 was 1.473 (1.228—1.769) (p < 0.001), and T2/T1 was 1.173 (0.976—1.409) (NS). NLR continuous was 1.054 (1.035—1.073) (p < 0.001). The multivariable Cox regression, from date of symptom onset, is summarized in . There was significant finding in categorical NLR T3/T2 1.040 (1.019—1.061) (p < 0.0001), and continuous 1.039 (1.016—1.064) (p < 0.001) analysis. Age of onset (p < 0.001), male sex (p = 0.021), bulbar region of onset (p < 0.001), and non-classical ALS (p < 0.001) were also significantly different among the tertiles.
Table 5. Univariable Cox-regression analysis of the Queensland ALS Cohort: NLR tertiles vs survival from date of symptom onset.
Table 6. Multivariable Cox-regression analysis of the Queensland ALS Cohort: NLR and variables vs survival from date of symptom onset.
We also analyzed the same cohort according to NLR cutoff value groups. This analysis is shown in and Supplementary Table 1. For age of onset, including comparison of early and late onset, there was a significant difference between Group 1 and Group 3 (p < 0.01), and between Group 2 and Group 3 (p < 0.01). There were more males in Group 1 than in Group 2 (p < 0.05).
Table 7. Comparison of NLR cutoff value groups versus survival from date of symptom onset in the Queensland ALS Cohort.
For survival from date of symptom onset, including comparison of short and long survivors, there was as significant difference between Group 1 vs Group 3, and Group 2 vs Group 3 (p < 0.05). There was no significant difference in survival between corresponding tertiles and groups. Survival curves of NLR value cutoff groups are shown in Supplementary Figure 1.
3.2.2. Comparison by sex
There were more significantly more males (n = 493; 60%) than females across all NLR tertiles, particularly in T2 (64%) and T3 (63%) (p = 0.007─0.009). The full cohort characteristics and NLR according to sex are shown in Supplementary Table 2 (males) and Supplementary Table 3 (females).
Comparison of NLR tertiles and survival from date of symptom onset, based on sex is summarized in . NLR tertile survival curves for each sex, are shown in . In the male cohort, survival in T3 was poorer compared with T1 (p = 0.002), and T2 (p = 0.025). In the female cohort, survival in T3 was poorer compared with T1 (p = 0.002). Comparing sex, males had significantly higher mean NLR in T1 (p = 0.003), and NLR T2 (p < 0.0001) compared with females. There was no significant difference between males and females for mean NLR in T3 and overall NLR. There was no significant difference in NLR tertile and survival based on sex.
Figure 4. Kaplan-Meier Curves comparing NLR tertiles and survival from date of symptom onset shown by sex in the Queensland ALS Cohort. T3 is associated with poorer survival in both females and males.
Table 8. Comparison of NLR tertiles versus survival from date of symptom onset, based on subject sex in the Queensland ALS Cohort.
Comparison of NLR cutoff value groups and survival, based on sex is summarized in Supplementary Table 4 and Supplementary Figure 2. In the male cohort, survival in Group 3 was significantly shorter than Group 1 (p = 0.0001), and Group 2 (p = 0.002). In the female cohort, survival in Group 3 was significantly shorter than Group 1 (p = 0.014), but no significant difference compared with Group 2. For each group, there was no significant difference shown between male and female for NLR mean and survival.
3.2.3. ROC curve analysis
The sensitivity and specificity of NLR and survival < 2 years, and < 5years, both from date of symptom onset and date of NLR, is shown in . Comparison by sex is shown in Supplementary Figure 3 and Supplementary Figure 4.
Figure 5. ROC Curves showing NLR and Survival in the Queensland ALS cohort from date of symptom onset, and date of first NLR. TOP: < 2 years survival. BOTTOM: < 5 years survival. In the cohort, 234 patients (28%) live less than 2 years, and 149 patients (18%) live more than 5 years.
For survival < 2 years from symptom onset, the area under the curve (AUC) was 58.4%. For NLR of 3.33, sensitivity was 41.7%, and specificity was 70%. For survival < 2 yrs from first NLR, the AUC was 64.2%. For NLR of 3.33, sensitivity was 40.9%, and specificity was 79.9%, for survival of <2years from the date of the test.
For survival <5 years from symptom onset, the AUC was 57.6%. For NLR of 3.33, sensitivity was 35.2%, and specificity was 75.2%. For survival < 5 years from NLR, the AUC was 64.6%. For NLR of 3.33, sensitivity was 35.2%, and specificity was 84.6% for survival < 5 years from the date of the test.
3.3. Meta-analysis
The first meta-analysis used subjects grouped in NLR tertiles. The second meta-analysis used subjects grouped according to NLR cutoff values. Mean values for the groups are shown in Supplementary Data Citation3.
In the first meta-analysis (), NLR T3 survival is significantly shorter when compared to NLR T1 (Log odds ratio 0.672; p < 0.05, I2 32.67), and NLR T2 (Log odds ratio 0.507; p < 0.05; I2 2.605). Comparison of survival of NLR T1 with T2 was not statistically significant.
Figure 6. Forest Plots showing meta-analysis comparing NLR Tertiles versus survival from date of symptom onset. NLR T3 shows significantly poorer survival compared with both T1 (B) and T2 (C). There is no significant survival difference between T1 and T2 (A).
In the second NLR meta-analysis (), Group 3 survival is significantly shorter when compared to Group 1 (Log odds ratio 0.958; p < 0.05, I2 88.200), and Group 2 (Log odds ratio 0.937; p < 0.05, I2 89.598). Comparison of survival of Group 1 and Group 2 was no statistically significant.
Figure 7. Forest Plots showing meta-analysis comparing NLR cutoff value groups versus survival from date of symptom onset. NLR Group 3 shows significantly poorer survival compared with both Group 1 (B) and Group 3 (C). There is no significant survival difference between Group 1 and Group 2 (A).
Further analyses, comparing mean cohort survival, are shown in Supplementary Figure 5 and Supplementary Figure 6.
4. Discussion
The aim of this paper was to investigate the use of NLR at time of diagnosis as a biomarker of survival in ALS. In the systematic review, we identified nine studies that reported the use of NLR as a biomarker. Six studies reported regression analysis of NLR versus survival, all all of these found an associated of NLR and survival (Citation26–29, Citation40–42). Four studies reported survival analysis (Citation26–29). These all showed that survival was worse in patients with higher NLR.
In our local cohort, we found that NLR was associated with survival. Cox regression analysis supported NLR as an independent risk factor, in addition to sex, region of onset, and disease type, comparable with similar studies (Citation26–29). Using survival analysis, we found that survival in NLR T3 was shorter than the mean survival of the whole cohort, and the survival of T1 and T2. The median age in T3 was greater that that of whole cohort T1, and T2. This is consistent with our previous analysis, which found that patients with shorter survival are older than those with longer survival (Citation6). When we examined males and females separately, we found that high NLR was associated with shorter survival in both sexes. We obtained similar results when patients were grouped into cutoff values NLR < 2, NLR 2-3 and NLR > 3.
There are issues with using NLR at diagnosis to predict survival from date of onset to date of death or censoring. The date of onset is not precise and depends on patient memory and the interval from date of onset to date of NLR testing is variable, as some patients have significant delay before diagnosis. Finally, we found that the NLR increases with the course of disease (Citation24, Citation40–42, Citation44). Therefore, to investigate the sensitivity of NLR in predicting survival, we investigated the relationship NLR with survival both from date of onset, and from the date of the test. We applied binary methods (Citation5, Citation47, Citation48) which are displayed as ROC curves. For these curves, the area under the curve was <70%. The best results came from analyzing the association of NLR with survival from the date of the test. High NLR was specific for short survival but not sensitive.
We also analyzed NLR and survival based on subject sex. Previous studies (Citation35) have shown lower neutrophil levels to be associated with a longer survival in females, compared with males. There was no significant difference between males and females in levels of neutrophils, or lymphocytes, however, males had a higher mean NLR in T1 and T2, compared with females. There was no survival difference comparing males and females in each tertile ( and ).
The meta-analyses showed that high NLR at disease diagnosiswas associated with significantly shorter survival. These studies do not show whether NLR causes reduced survival or whether NLR is elevated in patients with worse disease and shorter survival. We note that in our study, and in two studies included in the systematic review (Citation26–29), increased in NLR was associated with an increase in neutrophil numbers and a decline in lymphocyte numbers.
We will first discuss whether this association could be causal. This could occur if neutrophils are harmful and/or if lymphocytes are protective. Several studies have also shown that neutrophils are involved in ALS (Citation24, Citation41, Citation43, Citation49), and neutrophil numbers correlate with poor survival (Citation49, Citation50). Neutrophils have been associated with neurotoxicity through proinflammatory mechanisms (Citation51, Citation52). There are also reports of neutrophil accumulation in the spinal cord (Citation53), and that neutrophils can be associated with microglial dysfunction (Citation54). However, neutrophils could also be neuroprotective, with increased number and NLR representing innate neuronal repair process (Citation55, Citation56).
Increased neutrophils in ALS have also been described through studies of the neutrophil-to-monocyte ratio (NMR) (Citation27, Citation49). Monocyte involvement in ALS is also complex, with varying evidence across the cell subtypes, when measured as peripheral blood marker (Citation27, Citation49, Citation57). However, increased NMR, involving increased neutrophils, is associated with poorer survival (Citation27, Citation43, Citation49, Citation57) and decreased CD16 monocytes have been identified in ALS control studies subjects (Citation43, Citation49).
The association of higher NLR with shorter survival could also be related to reduced lymphocyte numbers. One study has shown that lymphocyte numbers are reduced in ALS, and that low numbers correlate with reduced survival (Citation49). Furthermore, increased lymphocyte with a lower NLR is associated with more advanced disease (Citation44). However, other studies have shown ALS onset and progression does not correlate with changes in lymphocyte levels (Citation40).
One possible explanation is that Treg cells are neuroprotective (Citation11, Citation58, Citation59), and decreased Treg numbers correlate with disease progression (Citation60, Citation61).
On the other hand, the association of NLR with worse prognosis could occur because increased NLR is a marker of severe illness and disordered physiology. Indeed, the association of NLR with worse survival is not specific and has been shown in Alzheimer’s Disease (Citation62), multisystem atrophy (Citation63), and progressive supranuclear palsy (Citation64). High NLR is also associated with increased mortality in other diseases, both acute and chronic (Citation65–69) which would be in keeping with high NLR being a nonspecific reaction to illness.
The strength to this study is that we provide a contemporary systematic review, provide data from another large patient cohort and performed the first meta-anlaysis of the topic. Limitations of the study are that our study cohort is retrospective, and that there is variability in the timing of NLR measurements, due to variability in the timing of presentation of patients.
In summary, this study has provided further evidence for the role of NLR as a biomarker of survival in ALS. The sensitivity and specificity is modest. The NLR can easily be applied in clinical practice, and deserves further investigation.
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References
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